scholarly journals Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chang Liu ◽  
Navindra P. Seeram ◽  
Hang Ma
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoints ◽  
Biochemical Assays ◽  
Programmed Death ◽  
Blocking Effects ◽  
Programmed Death 1 ◽  
Screening Assays ◽  
Leading Compounds

AbstractProgrammed death-1/programmed death ligand-1 (PD-1/PD-L1) based immunotherapy is a revolutionary cancer therapy with great clinical success. The majority of clinically used PD-1/PD-L1 inhibitors are monoclonal antibodies but their applications are limited due to their poor oral bioavailability and immune-related adverse effects (irAEs). In contrast, several small molecule inhibitors against PD-1/PD-L1 immune checkpoints show promising blockage effects on PD-1/PD-L1 interactions without irAEs. However, proper analytical methods and bioassays are required to effectively screen small molecule derived PD-1/PD-L1 inhibitors. Herein, we summarize the biophysical and biochemical assays currently employed for the measurements of binding capacities, molecular interactions, and blocking effects of small molecule inhibitors on PD-1/PD-L1. In addition, the discovery of natural products based PD-1/PD-L1 antagonists utilizing these screening assays are reviewed. Potential pitfalls for obtaining false leading compounds as PD-1/PD-L1 inhibitors by using certain binding bioassays are also discussed in this review.

Advances of biphenyl small-molecule inhibitors targeting PD-1/PD-L1 interaction in cancer immunotherapy

2021 ◽  
Author(s):  
Roufen Chen ◽  
Dandan Yuan ◽  
JunJie Ma
Keyword(s):  
Monoclonal Antibodies ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Biological Activities ◽  
Treatment Strategies ◽  
Structural Features ◽  
Great Promise ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
High Production Cost

Immunotherapy inhibiting the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) interaction has emerged as one of the most attractive cancer treatment strategies. So far, the clinically used PD-1/PD-L1 inhibitors are monoclonal antibodies, but monoclonal antibodies have several limitations, such as poor pharmacokinetic properties, unchecked immune responses and high production cost. The development of small-molecule inhibitors targeting PD-1/PD-L1 interaction is showing great promise as a potential alternative or complementary therapeutic approach of monoclonal antibodies. In this article, the authors classify the reported biphenyl small-molecule inhibitors into symmetrical and asymmetrical types based on their structural features and further review their representative inhibitors and biological activities, as well as the binding models for providing insight into further exploration of more potent biphenyl small-molecule inhibitors targeting PD-1/PD-L1 interaction.

scholarly journals Novel Small-Molecule Inhibitors of RNA Polymerase III

2003 ◽  
Vol 2 (2) ◽  
pp. 256-264 ◽  
Author(s):  
Liping Wu ◽  
Jing Pan ◽  
Vala Thoroddsen ◽  
Deborah R. Wysong ◽  
Ronald K. Blackman ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Rna Polymerase ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Rna Polymerase Iii ◽  
Wild Type ◽  
Biochemical Assays ◽  
Transcription In Vitro ◽  
Pol Iii

ABSTRACT A genetic approach utilizing the yeast Saccharomyces cerevisiae was used to identify the target of antifungal compounds. This analysis led to the identification of small molecule inhibitors of RNA polymerase (Pol) III from Saccharomyces cerevisiae. Three lines of evidence show that UK-118005 inhibits cell growth by targeting RNA Pol III in yeast. First, a dominant mutation in the g domain of Rpo31p, the largest subunit of RNA Pol III, confers resistance to the compound. Second, UK-118005 rapidly inhibits tRNA synthesis in wild-type cells but not in UK-118005 resistant mutants. Third, in biochemical assays, UK-118005 inhibits tRNA gene transcription in vitro by the wild-type but not the mutant Pol III enzyme. By testing analogs of UK-118005 in a template-specific RNA Pol III transcription assay, an inhibitor with significantly higher potency, ML-60218, was identified. Further examination showed that both compounds are broad-spectrum inhibitors, displaying activity against RNA Pol III transcription systems derived from Candida albicans and human cells. The identification of these inhibitors demonstrates that RNA Pol III can be targeted by small synthetic molecules.

scholarly journals Understanding Inflammasomes and PD-1/PD-L1 Crosstalk to Improve Cancer Treatment Efficiency

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3550
Author(s):  
Anaïs Perrichet ◽  
François Ghiringhelli ◽  
Cédric Rébé
Keyword(s):  
Cancer Treatment ◽  
Checkpoint Inhibitors ◽  
Response To Treatment ◽  
Immune Checkpoints ◽  
Cancer Growth ◽  
Inflammasome Activation ◽  
Treatment Efficiency ◽  
Programmed Death ◽  
Number Of Patients ◽  
Programmed Death 1

Inflammasomes and immune checkpoints have been shown to participate in carcinogenesis, cancer growth and response to treatment. Thus, targeting cytokines resulting from inflammasome activation, such as interleukin (IL)-1β, has emerged as a new tool in the therapeutic arsenal. Moreover, the use of checkpoint inhibitors such as anti-PD-1 or anti-PD-L1 has revolutionized the treatment of some cancer patients. However, inflammasome activation and consecutive cytokine release only occurs in some chemotherapeutic treatments and immune checkpoint inhibitors only work for a restricted number of patients, thus limiting the use of therapies targeting these pathways. Expanding knowledge about the inefficiency of these therapies recently brought forward the hypothesis of targeting both pathways. In this review, we provide an overview of the crosstalk between inflammasomes and programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) that might explain how these two pathways are mutually dependent, and perhaps why targeting only one of them leads to inefficiency of cancer treatment in some patients.

scholarly journals Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma

2015 ◽  
Vol 5 (5) ◽  
pp. e1100789 ◽  
Author(s):  
Hans A. Schlößer ◽  
Uta Drebber ◽  
Michael Kloth ◽  
Martin Thelen ◽  
Sacha I. Rothschild ◽  
...  
Keyword(s):  
Gastric Adenocarcinoma ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoints ◽  
Programmed Death ◽  
Programmed Death 1

scholarly journals Generation of Non-Nucleotide CD73 Inhibitors Using a Molecular Docking and 3D-QSAR Approach

2021 ◽  
Vol 22 (23) ◽  
pp. 12745
Author(s):  
Swapnil P. Bhujbal ◽  
Jung-Mi Hah
Keyword(s):  
Molecular Docking ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Structural Information ◽  
Structural Characteristics ◽  
Immune Surveillance ◽  
Experimental Studies ◽  
Adenosine Monophosphate ◽  
3D Qsar ◽  
Immune Checkpoints

Radiotherapy and chemotherapy are conventional cancer treatments. Around 60% of all patients who are diagnosed with cancer receive radio- or chemotherapy in combination with surgery during their disease. Only a few patients respond to the blockage of immune checkpoints alone, or in combination therapy, because their tumours might not be immunogenic. Under these circumstances, an increasing level of extracellular adenosine via the activation of ecto-5’-nucleotidase (CD73) and consequent adenosine receptor signalling is a typical mechanism that tumours use to evade immune surveillance. CD73 is responsible for the conversion of adenosine monophosphate to adenosine. CD73 is overexpressed in various tumour types. Hence, targetting CD73’s signalling is important for the reversal of adenosine-facilitated immune suppression. In this study, we selected a potent series of the non-nucleotide small molecule inhibitors of CD73. Molecular docking studies were performed in order to examine the binding mode of the inhibitors inside the active site of CD73 and 3D-QSAR was used to study the structure–activity relationship. The obtained CoMFA (q2 = 0.844, ONC = 5, r2 = 0.947) and CoMSIA (q2 = 0.804, ONC = 4, r2 = 0.954) models showed reasonable statistical values. The 3D-QSAR contour map analysis revealed useful structural characteristics that were needed to modify non-nucleotide small molecule inhibitors. We used the structural information from the overall docking and 3D-QSAR results to design new, potent CD73 non-nucleotide inhibitors. The newly designed CD73 inhibitors exhibited higher activity (predicted pIC50) than the most active compound of all of the derivatives that were selected for this study. Further experimental studies are needed in order to validate the new CD73 inhibitors.

scholarly journals A Robust Multiplex Mass Spectrometric Assay for Screening Small-Molecule Inhibitors of CD73 with Diverse Inhibition Modalities

2018 ◽  
Vol 23 (3) ◽  
pp. 264-273 ◽  
Author(s):  
Jessica McManus ◽  
Timothy He ◽  
Julie-Ann Gavigan ◽  
Ghislaine Marchand ◽  
Stephanie Vougier ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Small Molecule Inhibitors ◽  
Dynamic Range ◽  
Elevated Concentration ◽  
Antitumor Effects ◽  
Extracellular Adenosine ◽  
Biochemical Assays ◽  
Small Molecule Libraries

CD73/Ecto-5′-nucleotidase is a membrane-tethered ecto-enzyme that works in tandem with CD39 to convert extracellular adenosine triphosphate (ATP) into adenosine. CD73 is highly expressed on various types of cancer cells and on infiltrating suppressive immune cells, leading to an elevated concentration of adenosine in the tumor microenvironment, which elicits a strong immunosuppressive effect. In preclinical studies, targeting CD73 with anti-CD73 antibody results in favorable antitumor effects. Despite initial studies using antibodies, inhibition of CD73 catalytic activity using small-molecule inhibitors may be more effective in lowering extracellular adenosine due to better tumor penetration and distribution. To screen small-molecule libraries, we explored multiple approaches, including colorimetric and fluorescent biochemical assays, and due to some limitations with these assays, we developed a mass spectrometry (MS)-based assay. Only the MS-based assay offers the sensitivity and dynamic range required for screening small-molecule libraries at a substrate concentration close to the Km value of substrate and for evaluating the mode of binding of screening hits. To achieve a throughput suitable for high-throughput screening (HTS), we developed a RapidFire–tandem mass spectrometry (RF-MS/MS)-based multiplex assay. This assay allowed a large diverse compound library to be screened at a speed of 1536 reactions per 40–50 min.

scholarly journals Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jang-June Park ◽  
Emily P. Thi ◽  
Victor H. Carpio ◽  
Yingzhi Bi ◽  
Andrew G. Cole ◽  
...  
Keyword(s):  
T Cell ◽  
Small Molecule ◽  
Viral Infections ◽  
Checkpoint Inhibition ◽  
Humanized Mouse Model ◽  
Programmed Death Ligand 1 ◽  
Therapeutic Implications ◽  
Cell Responses ◽  
Programmed Death ◽  
Programmed Death 1

AbstractProgrammed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.

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